This application claims priority to Chinese Patent Application No. 00 1 17235.2, filed on Jul. 27, 2000.
This invention relates to pharmaceutical compositions and methods for the treatment of diseases associated with immune response in the anterior segment and the surface of the eye.
Diseases associated with immune response in the anterior segment and surface of the eye include erosive corneal ulcer, rejection reactions in cornea transplantation, allergic inflammation of conjunctiva and corneal limbus. At present, the medicines of choice for treatment of these diseases are glucocorticosteroids. These medicines, however, have strong side-effects after long-term topical administration. These side effects include skin atrophy, inhibition of healing of corneal epithelium and lesion, corticosteroid glaucoma, and complicated cataract.
Cyclosporin A (CsA) has been used as alternatives to glucocorticosteroid. Although CsA has good therapeutic effects on immune-response associated ocular surface diseases, recent research showed that CsA has limited local penetration. Consequently, immune inhibition in non-surface ocular tissues is primarily achieved via the systemic pharmacological effect of CsA. In addition, oil-based eye-drops of CsA have significant irritant effect on eyes.
Therefore, there is a need for novel pharmaceutical compositions that do not have the drawbacks of the present therapies.
The invention relates to a pharmaceutical composition for the treatment of immune-related diseases of ocular surface and the anterior segment of the eye. More specifically, the invention relates to a composition comprising tacrolimus in a pharmaceutically acceptable formulation, particularly a suitable local treatment formulation, such as eye drops, ointments. Also disclosed is a method for the treatment of immune-response related ocular diseases of the of the anterior segment of the eye and the eye surface, wherein the method comprises administering to a patient in need thereof the pharmaceutical composition of the present invention. The method of the present invention preferably further comprises administering to the patient an immunosuppressant in addition to tacrolimus.
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It suppresses both humoral and cellular immune responses. The drug inhibits a calcium/calmodulin-dependent phosphatase, calcineurin, which prevents the activation of T-cell-specific transcription factors that are involved in lymphokine expression. Other mechanisms are probably also involved in the pharmacologic and toxic effects of tacrolimus. (Schwaninger M et al. Naunyn Schmiedbergs Arch Pharmacol. 1993; 348: 541-545.)
Absorption of the drug from the gastrointestinal tract after administration of an oral dose is variable. The absorption half-life as measured in 16 patients is 5.7xc2x14.6 hours. Maximum blood and plasma concentrations are reached 1.5 to 3.5 hours after administration. Disposition of the drug is biphasic. The terminal elimination half-life is 11.7xc2x13.9 hours in transplant patients, compared with 21.2 hours in healthy volunteers.
Tacrolimus has a formula C44H69NO12.H2O, a molecular weight of 822D and its structure is as shown below: 
It is a white powder at room temperature, readily dissolved in organic solvents such as methanol, ethanol, and chloroform. It dissolves poorly in water.
Tacrolimus is a member of hydrophobic immunosuppressants in macrolide-type family. The family includes CsA, rapamycin (or sirolimus), and ascomycin. Administration in vitro demonstrates that its effect on immunosuppression is 10-100 folds of that of CsA. Clinically, it has been systemically applied with success to treat rejection in transplantation and autoimmune diseases, and has been routinely used in the transplantation of kidney, liver, and heart. When used systemically, however, tacrolimus has strong side effects similar to that of CsA. In addition, the relatively high dose required by the systemic administration incurs high costs.
As discussed above, presently, locally applied pharmaceutical compositions for the treatment of immune-response related eye diseases, especially those of the anterior or the surface of the eye, have strong, undesirable side effects. Other presently available pharmaceutical compositions rely on systemic administration and also have similar, strong undesirable side effects.
To date there has been no report that tacrolimus may be used for treating diseases associated with immune response in the anterior segment and the surface of the eye.
The inventions disclosed herein overcome the drawbacks of the severe topical side-effects of current therapeutic drugs for immune-response related ocular diseases, particularly the diseases of the anterior segment of the eye and the eye surface. The compositions and methods disclosed herein comprise the use of tacrolimus in a local or topical way. The present compositions and methods have better topical effect, but less toxic and other side effects.
According to the present invention, tacrolimus may be formulated in any pharmaceutical compositions suitable for topical administration, including eye drops, ointments, creams and powders. In a preferred embodiment, anhydrous tacrolimus is used.
In a preferred embodiment, the pharmaceutical composition of the invention is an eye drop. The most preferred composition of the eye drop comprises, in a 100 ml water solution, the following ingredients: 0.02-0.2 grams of tacrolimus; 0-1.5 grams of NaCl, pharmaceutically acceptable amounts of surfactant, and antibiotics or bacterial suppressant (collectively xe2x80x9cbacterial suppressantxe2x80x9d hereinafter), and a suitable amount of thickener to adjust the viscosity of the composition to 40-50 cP.
Suitable bacterial suppressant for the present invention may be any commonly used, pharmaceutically suitable one, except for phenylmercuric nitrate. Suitable concentrations for the bacterial suppressant can be determined by a skilled person according to routine procedures. For example, (1) thimerosal at a concentration of 0.02-0.04% g/ml; (2) quaternary ammonium salts, including geramine, bromogeramine, domiphen bromide, myristylpicolinin bromide, and chlorhexidine, whose effective concentrations are 0.002-0.01% (g/ml); (3) ethanols, such as trichlorbutanolum at 0.3-0.6% (g/ml); (4) nipagins at concentrations of 0.03-0.06% (g/ml); and (5) acids, such as sorbic acid with a concentration of 0.01-0.08% (g/ml).
A skilled artisan will recognize that any commonly used, pharmaceutically suitable thickener can be used for the present invention. Preferred examples include hydroxypropyl methylcellulose, sodium hyaluronide, polyvinyl alcohol, polyvinyl pyrrolidone. The degree of polymerization may be routinely controlled such that the eye drops achieve a final viscosity of 40-50 cP. It is obvious to those skilled in the art that an increased viscosity reduces eye irritation and prolong the residual time of the eye drops. There are many surfactants frequently used for ophthalmologic purposes and all of them are suitable for this invention. Examples include a polyoxyethylated castor oil (HCO60) with a dosage of 0.8-8.0% g/ml.
In a particularly preferred embodiment, the eye drop of the present invention may be prepared according to the following procedure. The thickener is dispersed in a suitable, small amount of water, and the solutions is cooled. Separately, the surfactant, sodium chloride, and bacterial suppressant are dissolved in water. The two solutions are then combined, mixed and filtered, and the volume is adjusted with water. Finally, tacrolimus is dissolved in the mixed solution and the resultant preparation is filtered and dispersed into individual packages.
According to another preferred embodiment, the pharmaceutical composition of the invention is an eye ointments. A most preferred eye ointment has the following composition:
The eye ointments of the invention may be prepared according to procedures known and used by those skilled in the art.
Another preferred embodiment of the pharmaceutical composition of the invention is an eye cream. According to a particularly preferred embodiment, the eye cream of the invention uses an oil-in-water emulsion as the medicament adjuvant. The eye cream of the invention may be prepared by procedures commonly used in the art.
The present invention further relates to methods for treating immune related ocular diseases, particularly the diseases of the anterior segment of the eye and the eye surface. According to the present invention, pharmaceutical compositions of the present invention comprising tacrolimus are applied topically and locally to the eye.
In rabbits, the methods of the instant invention achieves effective ocular penetration and regardless whether the composition is in the form of eye drops, ointments, or creams, the concentration of the active ingredient reaches therapeutically effective levels, in the target eye tissues, including aqueous humor, cornea, and conjunctiva.
In rats, ocular surface administrations of corticosteroid, tacrolimus, and CsA all show clear inhibition of immune rejection to allotypic transplantation of cornea. The therapeutic action of tacrolimus on cornea transplantation, however, can be elaborated via local immune regulation, thereby resulting in reduced side-effects and lowered cost
Clinical tests further demonstrate that the administration of tacrolimus has improved therapeutic effects on the diseases over other immunosuppressants.
The following examples further illustrate the compositions and methods of the instant invention.
The preparation procedure is as discussed above.
The production procedure is the same as above.
The production procedure is the same as above.
Eye ointment preparation is as follows: an appropriate amount of cool aseptic liquid paraffin is added into tacrolimus, grounded into fine cream, filtered with a size 6 sieve; then aseptic and filtered mixture of lanolin and yellow vaseline is gradually added and mixed thoroughly.
The preparation procedure is the same as example 4.